Recently, there has been a flurry of interest in what is termed a "molecular diversity" approach to finding new drug entities wherein organic synthesis is used to generate libraries of organic peptide and non-peptide compounds by incorporating a series of "building blocks," usually on a solid support utilizing the process known as solid-phase synthesis. Such libraries may be generated by covalently anchoring an organic compound which serves as a building block to a solid support such as a polymeric resin, silica, glass, cotton or cellulose; adding functional groups or other compounds onto the first compound; and cleaving the finished product from the solid support when the synthesis is complete. The compound may be attached to the solid support by means of a "linker." A linker can be any group that holds the starting material onto the solid support (or a molecule containing such a group), which is stable to the reaction conditions necessary to complete the synthesis and is easily cleavable upon completion of the synthesis. While there has been a growing evolution in the design of compounds to be used as building blocks for such libraries, there still remains a heavy reliance on ester and amide functionality for attaching the compounds to the support. While this may be suitable in some specific cases, it fails as a general strategy for the production of a library that incorporates only those functionalities necessary for biological activity. Those compounds that retain the vestiges of the amide linker may also be susceptible to hydrolysis by in vivo exopeptidases. This invariably would complicate the analysis for determining the essential active components in a drug lead. Finally, linkers that rely on ester or amide functionality, in many cases, require harsh cleavage conditions such as trifluoroacetic acid as part of their cleavage protocol. The total removal of trifluoroacetic acid, for example, typically requires one to incorporate in the cleavage protocol a series of ether precipitation steps. Such steps make automation difficult.
Since the early 1960s there has been a large amount of work done on photoactive protecting groups that, upon irradiation in solution, release the active groups. For example, it is known that one can make a Friedel-Crafts acylation of polystyrene to give an alpha bromo ketone that can be treated with a free carboxylic acid to give the resulting ester on the support. When this support is irradiated with 350 nm light, the carbon-oxygen bond breaks, regenerating the carboxylic acid S. Wang, J. Org. Chem,, (1976), 41:3258!.
This method was later improved upon by making a linker that incorporates the alpha bromo ketone and which can be attached to any support containing a free amine or alcohol. When irradiated with 350 nm light, the carbon-oxygen bond breaks, releasing the carboxylic acid from the support F. S. Tjoeng et al., Tetrahedron Lett., (1982), 23:4439!. It was originally believed that this method of synthesis produced only one isomer of the linker, but it was later discovered that three structural isomers of the linker had been produced F. Uggieri et al., J. Org. Chem. (1986), 51:97!.
It is also known that a carbon-nitrogen bond can be cleaved upon irradiation with 350 nm light. Upon irradiation, C-terminal N-methylated peptide amides may be isolated V. N. Pillai et al., Indian J. of Chemistry, (1988), 27B:1004!. However, a method for the photolytic cleavage of a carbon-sulfur (C-S) bond from a heterogeneous support has not yet been developed.
Thus there remains a need for the preparation of novel linkers and methods of cleaving the product compounds from solid supports that contain no vestigial functional groups such as carboxylic acid or an amide bond, and form a single pure isomer. Furthermore, such compounds and methods should be useful under conditions that can be easily automated, and in combination with commercially available supports allowing for in-situ cleavage and biological testing of scaffolds in an aqueous solvent.